MX2008014059A

MX2008014059A - Zero-order modified release solid dosage forms.

Info

Publication number: MX2008014059A
Application number: MX2008014059A
Authority: MX
Inventors: Suneel Kumar Rastogi; Justin Clark Meadows; Vishal Kumar Gupta
Original assignee: Mallinckrodt Inc
Priority date: 2006-05-09
Filing date: 2007-05-09
Publication date: 2008-11-14
Also published as: EP2020995A2; AU2007249947B2; AU2007249947A1; JP2009536654A; PL2457562T3; EP2457563A1; ES2627127T3; EP2457562B1; WO2007133583A2; PL2457563T3; US20190358164A1; CA2651798C; WO2007133583A3; MX350380B; EP2457562A1; ES2626632T3; CA2651798A1; US20090110728A1; EP2457563B1

Abstract

The invention comprises a solid dosage form for delivery of water soluble pharmaceutical agents. The solid dosage form comprises a matrix core containing the pharmaceutical agent and a hydrophobic material, and a coating containing a hydrophilic pore-forming agent and a hydrophobic polymer. The dosage form exhibits a zero-order release profile upon dissolution.

Description

FORMS OF SOLID DOSAGE OF MODIFIED RELEASE IN THE ORDER OF ZERO FIELD OF THE INVENTION The present invention relates to solid dosage forms of modified release suitable for the administration of a wide range of water soluble drugs at a rate of release in the order of zero and to a process for making them. More specifically, the invention relates to modified release tablets having a matrix core containing methylphenidate hydrochloride surrounded by a modified release coating. BACKGROUND OF THE INVENTION Modified release dosage forms, which are well known in the art, release their drug content gradually and over a prolonged period after the drug makes contact with an aqueous solution (e.g., in vitro dissolution). , or the gastrointestinal fluid. { in vivo). These dosage forms are advisable for treating various diseases because the desired concentration of the drug is maintained in vivo for longer periods compared to the immediate release dosage forms, allowing less frequent administration. In many release dosage formulations Ref.196617 prolonged, the rate of drug release initially increases rapidly followed by a decrease in said rate of release. This type of drug release is categorized as first-order release. Such formulations may not produce uniform levels of concentration of the drug in the bloodstream over a prolonged period. Release dosage forms in the order of zero are also known in the art. The term "release in the order of zero", "dissolution in the order of zero" or "velocity in the order of zero" refers to a rate of release of a drug from the solid dosage form after coming in contact with an aqueous environment, which is uniform or nearly uniform for a given period, regardless of the concentration of the drug in the dosage form. The release dosage forms in the order of zero generally allow for a lower frequency of administration compared to the less sustained or more uneven delivery dosage forms, thereby improving the patient's therapeutic compliance. Dosage forms with release in the order of zero generally provide maximum therapeutic value with minimal side effects. Although such dosage forms are advantageous, it has been difficult to formulate highly soluble drugs in water in such dosage forms because the drugs are susceptible to a phenomenon known as "drug discharge". The dosage form can release the drug rapidly at a high concentration, effectively "dumping" the drug into the bloodstream and potentially overdosing the patient. The coated matrix systems were created with the aim of achieving a zero order release of various active agents. Woodall et al., "Matrix Tablets Containing a Zero Order Dissolution Profile," The AAPS Journal, Vol. 7, No. 2, Abstract W5253 (2005) publish kinetics in the order of zero for a coated matrix tablet with a weight increase of 3% or 5% ethylcellulose. Porter et al., "Modified Relay Matrix Tablets Coated with a Modified-Release Film Coating: Comparison of Regular Tablets with a Mini-tablet Multiparticulate System," AAPS PharmSci, Vol. 4, No. 4, Abstract T3352 (2002) describe nuclei of Matrix containing chlorpheniramine maleate and HPMC, coated with an aqueous dispersion of ethylcellulose (SURELEASE ™), modified with a water-soluble polymer system (OPADRY ™), reported to have kinetics in the order of zero. The matrix core of a modified release dosage form is often prepared by a process of wet granulation. Wet granulation can include grinding the drugs and other ingredients, preparing a binder, mixing the binder with the milled ingredients to form a wet mass, coarse screening the wet mass, drying the wet mass to form granules, sieving the granules, mixing the granules subjected to sieving with lubricants or other excipients, extruding the mixture and compressing to obtain a solid dosage form. Wet granulation is a costly, slow process that requires many processing steps and important capital assets. U.S. Patent No. 6,673,367 reports the controlled release of methylphenidate from beads coated with a sustained release coating produced by various granulation methods. Alternatively, the methylphenidate hydrochloride is mixed with Lactose DT, Methocel, talc, magnesium stearate and optionally Eudragit L 100-55 and compressed directly in the form of uncoated tablets. Methylphenidate and methylphenidate hydrochloride are psychostimulants prescribed for the treatment of attention deficit disorder (ADD), the most common psychiatric disorder in children. The disorder is characterized by lack of attention and impulsivity and may be present with hyperactivity (ADHD) as well as cognitive problems and Learning. It is believed that the mechanism of action of methylphenidate includes blocking the uptake of increased levels of extracellular dopamine and norepinephrine in the transporters of the nerve terminals. The drug is a mild stimulant of the central nervous system with more prominent effects on mental activities than on motor skills. It has been reported that conventional forms of methylphenidate have maximum blood levels between 1 hour and 3 hours and have a half-life of 2 to 4 hours in adults and children. Formulations of methylphenidate with immediate release characteristics, such as Ritalin ™, are usually administered in the morning and afternoon to ensure that the child receives an adequate dose for a period of 8 to 12 hours. This requires administration during school hours, which is preferably avoided to improve patient compliance and possible dosing errors. Patient compliance can be a problem in schools that prohibit children from taking medication during school hours or that require administration only during times when a nurse is present. In addition, rapid release of the drug into the bloodstream results in a maximum dose for a short period of the day with a subsequent dose decrease. It is preferable considerably uniform release of the drug so that it affects the child essentially evenly throughout the day. There is a commercial form of sustained release methylphenidate (Ritalin ™ SR), but it has been reported to be less effective for early morning behavior management and is not more effective than immediate release dosage forms such as Ritalin ™. Adverse side effects from the use of methylphenidate include hypertension, tachycardia, angina, arthralgia, dyskinesia, fever, rash or urticaria, thrombocytopenia, blurred vision or other changes in vision, seizures, muscle cramps, Tourette's syndrome, toxic psychosis or loss of weight. The long-term effects of methylphenidate in children have not been well established. Therefore, it is desirable to maintain a more uniform plasma concentration in the bloodstream during school hours to avoid such side effects. It is also desirable to limit the use of the drug to the times when it is most necessary to further restrict the risk of side effects. There is a need for an oral dosage form of release in the order of zero methylphenidate hydrochloride or other water soluble drugs, with a release of the drug from 6 to 10 hours, for administration once a day. BRIEF DESCRIPTION OF THE INVENTION In summary, the present invention is directed to a solid dosage form comprising a matrix core and a modified release coating. The matrix core comprises a hydrophobic material and a water soluble pharmaceutical agent. The modified release coating surrounds the matrix core and comprises a hydrophobic polymer and a hydrophilic pore-forming agent. The solid dosage form is capable of releasing the pharmaceutical agent at a rate in the order of zero over a period of at least four hours after administration to a subject. Another aspect of the present invention is directed to a method of making a solid dosage form by mixing a hydrophobic material, between about 2 and 14% by weight of a water soluble pharmaceutical agent, a water soluble pharmaceutical agent, a filler optional, an optional release modifier, an optional lubricant and an optional slider to form a mixture; and the compression of the mixture. Yet another embodiment of the invention points to a method of making a solid dosage form by mixing a hydrophobic material, a water soluble pharmaceutical agent, an optional filler, a optional release modifier, an optional lubricant and an optional slider to form a mixture, the compression of the mixture to form a matrix core, the coating of the matrix core to form a barrier coating surrounding the matrix core, drying of the barrier coating, the coating of the matrix core, coated with a barrier coating, with a modified release coating and the drying of the modified release coating to form the solid dosage form. The barrier coating comprises a water soluble polymer, and the modified release coating comprises a hydrophobic polymer and a hydrophilic pore-forming agent. The solid dosage form is capable of releasing the pharmaceutical agent at a rate in the order of zero over a period of at least four hours after administration to a subject. Yet another embodiment of the invention points to a method of making a solid dosage form by mixing a hydrophobic material, a water-soluble pharmaceutical agent, an optional filler, an optional release modifier, an optional lubricant and a glidant. optional to form a mixture, the compression of the mixture to form a matrix core, the coating of the matrix core with a modified release coating surrounding the matrix core and the drying of the modified release coating to form the solid dosage form. The modified release coating comprises a hydrophobic polymer and a hydrophilic pore-forming agent. The solid dosage form is capable of releasing the pharmaceutical agent at a rate in the order of zero over a period of at least four hours after administration to a subject. BRIEF DESCRIPTION OF THE FIGURES Figure 1A is a graph illustrating the percentage of dissolved methylphenidate hydrochloride as a function of time for the uncoated matrix core tablets, as described in Example 1. Figure IB is a graphic representation of ln (100 -% dissolved methylphenidate hydrochloride) as a function of time indicating a release of the first order drug for the uncoated tablets. Figure 2A is a graph illustrating the percentage of dissolved methylphenidate hydrochloride as a function of time for the coated tablets (ethylcellulose: hypromellose - 70:30), as described in Example 1. Figure 2B is a graphic representation of ln (100 -% dissolved methylphenidate hydrochloride) as a function of time indicating a release of the drug in the order of zero for coated tablets (ethylcellulose: hypromellose - 70:30). Figure 3 is a graph illustrating the percentage of dissolved methylphenidate hydrochloride as a function of time, as described in Example 2 for uncoated matrix core tablets. Figure 4A is a graph of the percentage of dissolved methylphenidate hydrochloride as a function of time, as described in Example 2 for coated tablets (ethylcellulose: hypromellose - 70:30) containing glyceryl behenate. Figure 4B is a graphical representation of ln (100 -% dissolved methylphenidate hydrochloride) as a function of time and indicates drug release in the order of zero for 6% and 8% tablets containing behenate glyceryl. Figure 5A is a graph of the percentage of dissolved methylphenidate hydrochloride as a function of time, as described in Example 3 for coated tablets (ethylcellulose: hypromellose - 80:20). Figure 5B is a graphic representation of ln (100 -% dissolved methylphenidate hydrochloride) as a function of time indicating a release of the drug in the order of zero for tablets with 4% modified release coating (ethylcellulose: hypromellose - 80:20). Figure 6 is a graph of the percentage of dissolved methylphenidate hydrochloride as a function of time, as described in Example 4 for tablets coated with ethylcellulose: hypromellose 95: 5. Figures 7 and 8 are graphs of the percentage of dissolved methylphenidate hydrochloride as a function of time, as described in Example 5 for tablets with 4% hypromellose sealer coating (ethylcellulose: hypromellose - 70:30). Figure 9 is a graph of the percentage of dissolved methylphenidate hydrochloride as a function of time, as described in Example 5 for tablets with 4% hypromellose sealant coating (ethylcellulose: triacetin: hypromellose - 70: 3.5: 26.5) . Figures 10 and 11 are plots of friability as a function of hardness for the uncoated matrix core tablets as described in Example 6, where 0.80% is the USP limit for 100 revolutions. Figures 12 and 13 are graphs of the percentage of dissolved methylphenidate hydrochloride as a function of time, as described in Example 6 for uncoated matrix core tablets of various hardnesses formed under various compression forces. Figures 14 and 15 are graphs of the percentage of dissolved methylphenidate hydrochloride as a function of time, as described in Example 8 for tablets Methylphenidate hydrochloride coatings. DETAILED DESCRIPTION OF THE INVENTION The present invention provides a modified dosage solid dosage form of a highly water soluble pharmaceutical ingredient, such as methylphenidate or a salt thereof, which exhibits a zero order kinetics upon dissolution. Said dosage form eliminates the need for administration twice a day, improves the likelihood of the patient's therapeutic compliance and establishes a dose of the drug substantially uniform throughout the period of 6 to 10 hours of efficacy following its administration. It also prevents or minimizes the risk of rapid absorption and accidental overdose due to inadequate dissolution of the dosage form. In the unlikely event that the coating of the dosage form is broken, drug release from the core is still controlled by the hydrophobic matrix material. Moreover, the solid dosage form can be easily processed under ambient conditions with minimum requirements in terms of processing steps and equipment. The solid dosage form of the invention comprises a matrix core, an optional barrier coating and a modified release coating. The matrix core is composed of an agent pharmaically active water soluble, a hydrophobic material and optional excipients such as fillers, release modifiers, lubricants, glidants and the like. If there is no barrier coating present, the modified release coating surrounds the matrix core. The modified release coating is composed of a hydrophobic polymer, a hydrophilic pore-forming agent, and an optional plasticizer. The term "pore-forming agents" includes materials that can be dissolved, extracted or filtered from the modified release coating in the environment of use. In one embodiment of the invention, the solid dosage form includes a barrier coating surrounding the matrix core. The barrier coating, also described herein as a sealant coating, is composed of a water soluble polymer and serves as a barrier between the pharmaical agent in the matrix core and the modified release coating. It has been found that such a barrier can be effective to maintain the integrity of the matrix tablet as well as the modified release coating in a tablet subjected to conventional storage conditions, as described below in example 3. Solid dosage forms of the present invention provide a release in the order of zero of the pharmaical agent after dissolution. When the dosage form is exposed to digestive liquids or other liquids, the liquid diffuses through the modified release coating, dissolving the hydrophilic pore-forming agent to form pores or channels in the modified release coating. The liquid continues to diffuse through the barrier coating (if present) and the matrix core, dissolving the pharmaical agent included in the matrix core. The pharmaical agent travels through the pores of the modified release coating out of the dosage form. The matrix core includes a pharmaically active agent, a hydrophobic material and fillers, release modifiers, lubricants and optional glidants. The pharmaically active agent that is within the matrix core can be any water-soluble pharmacologically active compound. Examples of such active agents suitable in the present invention include antihistamines, antibiotics, antituberculous agents, cholinergic agents, antimuscarinics, sympathomimetics, sympatholytics, autonomic drugs, iron preparations, hemostats, drugs for heart problems, antihypertensives, vasodilators, non-spheroidal anti-inflammatories, agonists opioids, anticonvulsants, tranquilizers, stimulants, barbiturates, sedatives, expectorants, antiemetics, drugs for the digestive system, heavy metal antagonists, antithyroid agents, smooth muscle relaxants and vitamins. Suitable water-soluble active agents include, but are not limited to, abacavir sulfate, acyclovir, aminocaproic acid, alendronate sodium, amitriptyline hydrochloride, amphetamine, acetaminophen, allopurinol, amoxicillin, atenolol, atropine sulfate, azithromycin, balsalazide, benzepril hydrochloride. , bisoprolol fumarate, bupropion hydrochloride, buformin, calaciclovir, captopril, cefprozil, cetrizine hydrochloride, cimetidine, ciprofloxacin, clindamycin, chlorpheniramine maleate, chlorpromazine hydrochloride, clomipramine hydrochloride, clonidine hydrochloride, clopidogrel bisulfate, cloxacillin sodium, codeine phosphate, colchicines, cyclophosphamide, diethylcarbamazine citrate, diltiazem, doxycycline, doxypin, DL-methionine, eprosartan, ethembutol hydrochloride, ethosuximide, erythromycin, fexofenadine, ferrous sulfate, fluoxetine hydrochloride, fluvastatin, fosinopril sodium, gabapentin, hydrochloride hydralazine, hydrocodone bitartrate , hydroxycin hydrochloride, hydroxyurea, indinavir sulfate, isoniazid, isosorbide mononitrate, lactobionate, lamivudine, levamisole hydrochloride, levofloxacin, lisinopril, losartan potassium, metformin hydrochloride, methylphenidate, methylphenidate hydrochloride, metoprolol tartrate, minocycline hydrochloride, montelukast sodium, naproxen sodium, neostigmine bromide, nicotinamide, niacin, nifurtimox, nortriptyline hydrochloride, olanzepine, oxybutynin chloride, penicillamine, penicillin V potassium, sodium phenytoin, phenformin, pramipexole, pravastatin sodium, potassium chloride, primaquine phosphate, promethazine, promethazine hydrochloride, propanolol hydrochloride, propoxyphene hydrochloride, pseudoephedrine hydrochloride, pyridostigmine bromide, pyridoxine hydrochloride, quinapril hydrochloride, quetiapine, ramipril, ranitidine hydrochloride, reboxetine, risedronate sodium, rosiglitazone maleate, sildenafil, sodium valproate, salbutamol sulfate, stavudine, sumanirol, sumatriptan succinate, terazosin hydrochloride, tetracycline hydrochloride, timolol maleate, tramadol hydrochloride, valaciclovir hydrochloride, van comicin, venlafaxine hydrochloride, verapamil hydrochloride, warfarin sodium or combinations thereof. Highly water soluble drugs, such as methylphenidate and its salts including methylphenidate hydrochloride, benefit most from the dosage form of the invention. The pharmaceutical agent is present in an amount between about 2% by weight and about 25% by weight of the total weight of the core of uncoated matrix, preferably between about 4% by weight and about 16% by weight, and more preferably between about 5% by weight and about 11% by weight. The hydrophobic material within the matrix core acts as a retarder of the rate of release. The hydrophobic material can be any hydrophobic material that does not dilate. Non-limiting examples of suitable hydrophobic materials include a glyceride (eg, glyceryl behenate, glyceryl trimyristate, glyceryl trilaurate, glyceryl tristearate, glyceryl monostearate, glyceryl palmito stearate or glyceryl triacetate), a hydrogenated castor oil, a hydrogenated vegetable oil, a water-insoluble cellulose (for example, ethylcellulose, cellulose acetate, cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate butyrate, cellulose acetate propionate, nitrocellulose, cellulose diacetate or cellulose), a wax or a wax-like substance (for example, carnauba wax, cetyl ester wax, beeswax, castor wax, cationic emulsifying wax, emulsifying wax of cetrimide, an emulsifying wax, microcrystalline wax, a wax non-ionic, a non-ionic emulsifying wax, paraffin wax, petroleum wax, petroleum wax ceresin, ball sperm wax ena, white wax or wax yellow), a fat, an oil, a fatty acid, an emulsifier, a modified starch, a fatty alcohol, a protein (for example, zein), a lacquer or a polymer (for example, a polyolefin, a polyurethane, a polyvinyl, a polyvinyl acetate, a polymer of acrylic acid or a polymer of methacrylic acid). These and other suitable hydrophobic materials are described in Kibbe, Authur H., Handbook of Pharmaceutical Excipients, 3rd Ed. (2000) and Remington's Pharmaceutical Sciences, 18th Ed. (1990), and are incorporated herein by reference. Preferably the hydrophobic material is ethylcellulose, such as AQUALON ™ TIO EC, and / or glyceryl behenate, such as COMPRITOL ™ 888 ATO. The hydrophobic material is present in an amount between about 10% by weight and about 50% by weight of the total weight of the uncoated matrix core, preferably between about 12% by weight and about 40% by weight, and more preferably between about 19% by weight and approximately 30% by weight. The matrix core may also include a release modifier to modify the release rate of the pharmaceutical agent from the matrix core. Examples of release modifiers include, but are not limited to, hydrophilic celluloses (e.g., hydroxypropylcellulose, hypromellose, hypromellose phthalate, methylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, carboxymethyl hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, ethyl methyl cellulose, methyl hydroxyethyl cellulose or propyl hydroxymethyl cellulose); saccharides (for example, pullulan, dextrin, sucrose, glucose, fructose, mannitol, lactose, mannose, galactose or sorbitol); polysaccharides (for example, polydextrose, guar gum, hydroxypropyl guar, alginate, polysorbate, xanthan gum or carboxymethyl hydroxypropyl guar), polyvinyl pyrrolidone and zein. Preferred release modifiers include high viscosity hydroxypropylcellulose (KLUCEL ™ HXF) and low viscosity hydroxypropylcellulose (KLUCEL ™ EF). When included, the release modifier is present in an amount up to about 40% by weight, between about 5% by weight and about 20% by weight, between about 3% by weight and about 17% by weight of the total weight of the product. core not coated with matrix, preferably between about 4% by weight and about 14% by weight, and more preferably between about 5% by weight and about 10% by weight. In some embodiments, the release modifier is present in an amount between about 10% by weight and about 17% by weight. The matrix core of the solid dosage forms of the present invention may include at least one pharmaceutically acceptable filler as an excipient. He The term "fillers" as used herein means fillers or binders that are used for current pharmaceutical production and include excipients that facilitate the flow and compression of powdered materials and give strength to solid dosage forms. The following are non-limiting examples of suitable fillers that can be used in the matrix core of the present invention: microcrystalline cellulose, sodium citrate, dicalcium phosphate, colloidal silicon dioxide, starches, lactose, sucrose, glucose, mannitol and silicic acid , alginates, gelatin, polyvinylpyrrolidinone, lactitol, dextrose, acacia, hypromellose, hydroxypropylcellulose, hydroxyethylcellulose, starch and pregelatinized starch, with microcrystalline cellulose, such as PROSOLV ™ HD90, which is preferred in some embodiments. The filler may be present in an amount up to about 75% of the total weight of the uncoated matrix core. The content of filler in the matrix core can be increased or decreased based on various factors such as the pharmaceutical agent loading, the solubility of the pharmaceutical agent and the desired release profile. When a filler is included, the filler is generally present in an amount between about 50% and about 75%, preferably between about 50% by weight and about 70% by weight, and more preferably between about 50% by weight and about 65% by weight or even between about 50% by weight and about 58% by weight. The matrix core of the solid dosage form of the present invention may further include at least one pharmaceutically acceptable lubricant as excipient. The term "lubricant" as used herein includes excipients that reduce friction, heat, and wear when applied as a surface coating to moving parts within the equipment that is used to make the dies, such as molds and punches. Suitable lubricants include, either individually or in combination, a glyceride (e.g., glyceryl behenate (e.g., Compritol ™ 888 ATO), glyceryl trimyristate, glyceryl trilaurate, glyceryl tristearate, glyceryl monostearate, glyceryl palmito stearate. or glyceryl triacetate); Stearic acid and its salts, including stearates of magnesium, calcium, aluminum, zinc and sodium; hydrogenated vegetable oils (eg, Sterotex ™); colloidal silica; talcum powder; waxes; boric acid; sodium benzoate; sodium acetate; sodium fumarate; DL-leucine; polyethylene glycol (for example, Carbo ax ™ 4000 and Carbo ax ™ 6000); sodium oleate; sodium lauryl sulfate; and magnesium lauryl sulfate. The lubricant is preferably selected from the group consisting of the salts of stearic acid such as calcium stearate and magnesium stearate, stearic acid, sodium stearyl fumarate, solid polyethylene glycols, sodium lauryl sulphate and their mixtures. Magnesium stearate is a particularly preferred lubricant. When present, the amount of lubricant in the matrix core is between about 0.5% by weight and about 5% by weight of the total weight of the uncoated matrix core, preferably between about 0.5% by weight and about 3% by weight, and more preferably between about 1% by weight and about 2% by weight. The matrix core may also include a slider to improve the flow of the mixture through the hopper used to make the dies. Suitable glidants include colloidal silicon dioxide (such as Cab-O-Sil ™, M5), aluminum silicate, talc, powdered cellulose, magnesium trisilicate, silicon dioxide, kaolin, glycerol monostearate, metal stearates such as stearate magnesium, titanium dioxide and starch. Colloidal silicon dioxide is a preferred glidant. When present, the amount of slider in the matrix core is between about 1% by weight and about 10% by weight of the total weight of the uncoated matrix core, preferably between about 2% by weight and about 7% by weight, and more preferably between about 2% by weight and about 4% by weight.

Other excipients that can be used in the matrix core, such as colorants, flavors, sweeteners and stabilizers, are known in the pharmaceutical art and can be used in the compositions of the present invention. In some embodiments, the matrix core comprises between about 10 and about 50% by weight of hydrophobic material, between about 2 and about 25% by weight of water soluble pharmaceutical agent, up to about 5% by weight of lubricant, up to about 75. % by weight of filler, up to about 25% by weight of modifier of the release and up to about 10% by weight of slider. In some other embodiments, the matrix core comprises between about 12 and about 40% by weight of hydrophobic material, between about 4 and about 16% by weight of water soluble pharmaceutical agent, between about 0.5 and about 3% by weight of lubricant , between about 50 and about 70% by weight of filler, between about 5 and about 20% by weight of release modifier, and up to about 7% by weight of glidant. In still other embodiments, the matrix core comprises between about 19 and about 30% by weight of hydrophobic material, between about 5 and about 11% by weight of water soluble pharmaceutical agent, among about 1 and about 2% by weight of lubricant, between about 50 and about 58% by weight of filler, between about 10 and about 17% by weight of release modifier, and up to about 4% by weight of glidant. The barrier coating of the solid dosage form, if included, comprises a water-soluble polymer and optional non-sticks or optional viscosity enhancers. The water-soluble polymer of the barrier coating can be any water-soluble polymer and is preferably a highly water-soluble polymer. Suitable materials that can be used as a barrier coating include hypromellose, hypromellose phthalate, methylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylhydroxyethylcellulose, ethylhydroxyethylcellulose, ethyl methylcellulose, hydroxyethyl methylcellulose, hydroxymethylcellulose, hydroxymethylpropyl cellulose, alcohol polyvinyl, polyvinylpyrrolidone, a polyalkylene oxide, a polyalkylene glycol, an acrylic acid polymer, a vinyl acetate copolymer, a polysaccharide, a methacrylic acid copolymer or a maleic anhydride / methyl vinyl ether copolymer. In one embodiment, the barrier coating contains hypromellose. When present, the barrier coating is used in an amount which represents an increase in weight between about 2.0% by weight and about 6.0% by weight of the total weight of the uncoated matrix core, preferably between about 3% by weight and about 5% by weight, and more preferably between about 3.5% by weight weight and approximately 4.5% by weight. In some embodiments, the barrier coating may include a release agent to reduce the agglomeration of the coating during application. Non-limiting examples of antiadhesives that can be used in the barrier coating include talc, glyceryl monostearate, magnesium stearate, calcium stearate, stearic acid and mixtures thereof. When present, the amount of release agent in the barrier coating is between about 5% by weight and about 50% by weight based on the total weight of the barrier coating. Other excipients that can be used in the barrier coating, such as viscosity modifiers, are known in the pharmaceutical art and can be used in the compositions of the present invention. The modified release coating includes a hydrophobic polymer, a hydrophilic pore-forming agent, and optional plasticizers and antiadhesives. Any hydrophobic polymer can be used in the modified release coating of the solid dosage form. HE they prefer polymers that do not swell. Suitable hydrophobic polymers that can be used in the modified release coating of the present invention include, but are not limited to, ethylcellulose, cellulose acetate, cellulose acetate butyrate, cellulose acetate propionate, nitrocellulose, polyvinyl chloride, polyvinyl acetate, polymethylmethacrylate, polyethylacrylate, polyacrylates, polymethacrylates such as Eudragit ™ (a copolymer of ammonium methacrylate obtainable from Rohm Pharma, Darmstadt, Germany), polyvinyl chloride, polyethylene, polypropylene, polyisobutylene, trimethylammonium polymethyl methacrylate or a polymer or copolymer in block of these. The hydrophobic polymer is present in an amount between about 5% by weight and about 70% by weight of the total weight of the modified release coating, preferably between about 20% by weight and about 60% by weight, and more preferably between about 25% in weight and approximately 55% by weight. Ethylcellulose is a preferred hydrophobic polymer that can be used in the modified release coating. The ethylcellulose may be a common dispersion of ethylcellulose containing ethylcellulose, a suitable plasticizer, and stabilizers. An example of a dispersion of ethylcellulose of suitable quality can be obtained from Colorcon Inc. of West Point, Pa. , with the name commercial SURELEASE ™, which contains approximately 25% by weight solids. Any hydrophilic pore forming agent in the modified release coating can be used and can be solid or liquid. Suitable pore-forming agents include, but are not limited to, a polymer (for example, polyvinylpyrrolidone, a polyalkylene oxide or a polyalkylene glycol), a cellulose or a cellulose ether (for example, hypromellose, hypromellose phthalate, methylcellulose, carboxymethylcellulose). sodium, hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, ethyl methyl cellulose, hydroxyethyl methyl cellulose, hydroxymethyl cellulose or hydroxymethyl propyl cellulose), a protein, a protein derivative, a saccharide (for example, pullulan, dextrin, sucrose, glucose, fructose, mannitol, lactose, mannose, galactose or sorbitol), a polysaccharide (for example, polydextrose, guar gum, hydroxypropyl guar, alginate, xanthan gum or carboxymethyl hydroxypropyl guar), an alkali metal salt (for example, lithium carbonate, sodium chloride, sodium bromide, potassium chloride, potassium sulfate, potassium phosphate, sodium acetate or sodium citrate). The hydrophilic pore forming agent is present in an amount between about 30% by weight and about 95% by weight of the total weight of the release coating modified, preferably between about 40% by weight and about 80% by weight, and more preferably between about 45% by weight and about 75% by weight. Preferably, the pore-forming agent is a hydroxyalkyl alkyl cellulose, carboxymethyl cellulose or a salt thereof, such as hydroxyethyl methyl cellulose, hypromellose, carboxymethyl cellulose or sodium carboxymethyl cellulose. Most preferably, the water soluble component is hypromellose, such as OPADRY ™ (marketed by Colorcon, West Point, Pa.). In some embodiments, the modified release coating may include an anti-adherent to reduce the agglomeration of the coating during application. Non-limiting examples of anti-adherents that can be used in the modified release coating include talc, glyceryl monostearate, magnesium stearate, calcium stearate, stearic acid and mixtures thereof. When present, the amount of release agent in the modified release coating is between about 5% by weight and about 50% by weight based on the total weight of the modified release coating. In one embodiment, the modified release coating includes SURELEASE ™ (available from Colorcon) as the hydrophobic polymer and OPADRY ™ (which can be get from Colorcon) as the pore-forming agent. Weight ratios of 70:30, 80:20, 90:10 and 95: 5 were evaluated between SURELEASE ™ and OPADRY ™, but coatings with 80% or more of SURELEASE ™ presented a variable release in some coatings. When the nuclei are coated with ethylcellulose and hypromellose at ratios less than 80:20, the desired profile of drug release with characteristics in the order of zero is achieved. In some cases, the modified release coating contains between about 5 and about 70% by weight of hydrophobic polymer, between about 30 and about 95% by weight of hydrophilic pore forming agent, up to about 40% by weight of plasticizer and up to about 50% by weight. % by weight of non-stick. In other cases, the modified release coating includes between about 20 and about 60% by weight of hydrophobic polymer, between about 40 and about 80% by weight of hydrophilic pore forming agent, between about 20 and about 35% by weight of plasticizer , and up to 20% by weight of non-stick. In still other cases, the modified release coating comprises between about 25 and about 55% by weight of hydrophobic polymer, between about 45 and about 75% by weight of hydrophilic pore forming agent, between about 20 and about 30% by weight. plasticizer weight, and up to 10% by weight of non-stick. In one embodiment of the invention, the weight ratio between hydrophobic polymer and hydrophilic pore-forming agent is between about 1: 1 and about 9: 1, between about 1: 1 and about 4: 1, between about 1: 1 and about 3: 1, and preferably between approximately 1.25: 1 and approximately 2.33: 1. In the results of Example 3, it was discovered that the polymeric coating of mixtures of the hydrophilic hydrophobic and hydrophilic ethylcellulose polymers is susceptible to film cracking. This can lead to changes in the dissolution profile when storing. The cracking of the film can be prevented by imparting flexibility to the modified release coating and / or by adding plasticizer. SURELEASE ™ and OPADRY ™ both contain some plasticizer. However, an additional amount of at least about 4, 5, 6, 7, 8, 9 or 10% by weight or more of plasticizer is added to avoid the coating cracking under storage conditions, as shown by the results of the Example 3. Any plasticizer can be used for the coatings of the tablets. Examples of plasticizers are triacetin, methyl abietate, acetyl tributyl citrate, acetyl triethyl citrate, diisooctyl adipate, amyl oleate, butyl ricinoleate, benzoate of benzyl, butyl and glycol esters of fatty acids, butyl carbonate and diglycol, butyl oleate, butyl stearate, di (β-methoxyethyl) adipate, dibutyl sebacate, dibutyl tartrate, diisobutyl adipate, dihexyl adipate , di (2-ethylbutyrate) of triethylene glycol, di (2-ethylhexoate) of polyethylene glycol, diethylene glycol monolaurate, monomeric polyethylene ester, hydrogenated rosin methyl ester, methoxyethyl oleate, butoxyethyl stearate, butyl phthalyl butyl glycolate, tributyrate glycerol, triethylene glycol dipelargonate, β- (p-ter-amylphenoxy) ethanol, β- (p-tert-butylphenoxy) ethanol, β- (p-tert-butylphenoxyethyl) acetate, bis ^ -p-tert-butylphenoxydiethyl ether) , camphor, a petroleum based hydrocarbon, diamyl phthalate, (diamylphenoxy) ethanol, diphenyl oxide, hydrobicylalcohol, becolin, acetyl tributyl citrate, polyethylene glycol, blown castor oil or glyceryl triacetate. In one embodiment, the plasticizer was triacetin. When present, the amount of plasticizer added in the release coating is between about 3% by weight and about 20% by weight of the total weight of the modified release coating, preferably between about 4% by weight and about 15% by weight, and more preferably between about 5% by weight and about 10% by weight. When present, the amount of total plasticizer in the release coating is between about 20% by weight and about 40% by weight of the total weight of the modified release coating, preferably between about 20% by weight and about 35% by weight, and more preferably between about 20% by weight and about 30% by weight. The solid dosage form of the invention may optionally include an overcoat to provide an initial release dose of a pharmaceutical agent. The overcoat contains any pharmaceutical agent, a water-soluble polymer, an optional non-stick, an optional plasticizer, an optional stabilizer and an optional viscosity enhancer. The overcoat, if present, is applied to the matrix core tablet, optionally coated with barrier coating, coated with modified release coating. Examples of said active agents include any water insoluble drug, as well as any water soluble drug such as those mentioned above in relation to the pharmaceutical agent of the matrix core. In some cases, a water-soluble pharmaceutical agent is preferred in the overcoat. In some embodiments, the pharmaceutical agent within the overcoat is the same pharmaceutical agent included in the matrix core. In other modalities, the agent Pharmaceutical within the envelope coating is different from the pharmaceutical agent included in the matrix core. In some embodiments, the pharmaceutical agent is not very soluble in water and forms a suspension instead of a solution with the water soluble polymer. The particle size of the pharmaceutical agent and other undissolved components in said overcoating suspension can be in the micrometer range to minimize settling of these components in the suspension and to maintain a homogeneous suspension. The water-soluble polymer of the overcoat can be any water-soluble polymer and is preferably a highly water-soluble polymer. Suitable materials that can be used in overcoating include hypromellose, hypromellose phthalate, methylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethylhydroxyethylcellulose, ethylhydroxyethylcellulose, ethyl methylcellulose, hydroxyethyl methylcellulose, hydroxymethylcellulose, hydroxymethylpropyl cellulose, alcohol polyvinyl, polyvinylpyrrolidone, a polyalkylene oxide, a polyalkylene glycol, an acrylic acid polymer, a vinyl acetate copolymer, a polysaccharide, a copolymer of methacrylic acid or a copolymer of maleic anhydride / methyl vinyl ether. In some modalities, the envelope coating contains hypromellose. When present, the overcoat is used in an amount representing an increase in weight between about 2% by weight and about 25% by weight of the total weight of the solid overcoated dosage form, preferably between about 4% by weight and about 12% by weight, and more preferably between about 5% by weight and about 6.5% by weight. The overcoating may contain a plasticizer. Any plasticizer can be used for the tablet coatings. Examples of plasticizers are those described above for overcoating. In some embodiments, the plasticizer is triacetin or polyethylene glycol. When present, the amount of plasticizer in the overcoat is between about 5% by weight and about 30% by weight of the total weight of the overcoat. In some embodiments, the overcoat may include a release agent to reduce the agglomeration of the coating during application. Non-limiting examples of anti-adherents that can be used in the overcoat include talc, glyceryl monostearate, magnesium stearate, calcium stearate, stearic acid and mixtures thereof. When present, the amount of nonstick in the overcoat is between about 5% by weight and about 50% by weight based on the total weight of the overcoat. The overcoat may include an optional stabilizer to minimize or prevent degradation of the pharmaceutical agent in the overcoat. Any pharmaceutically acceptable compound that minimizes the degradation of the pharmaceutical agent in the overcoat can be used. For example, an acidic compound such as hydrochloric acid or fumaric acid can be used to stabilize the pharmaceutical agent when the pharmaceutical agent is more stable at acidic pH. For example, an acid can be used to stabilize methylphenidate. One skilled in the art could easily identify suitable stabilizers for the particular active agents of the dosage forms of the invention. When present, the amount of stabilizer in the overcoat is between about 1% by weight and about 10% by weight based on the total weight of the overcoat. The overcoat may also include an optional viscosity enhancer to reduce the settling of the pharmaceutical agent in the overcoat, in particular when the overcoat is applied as a suspension rather than as a solution. Non-limiting examples of viscosity enhancers that they can be used in the overcoat include a sugar (dextrose, glucose and sucrose), a cellulose derivative such as carboxymethylcellulose and sodium or calcium hydroxypropylcellulose, a polysaccharide, a pectin, agar, carrageenan, a hydrophilic gum like gum acacia, guar gum, gum arabic and xanthan gum, alginic acid, an alginate, dextrin, a carbomer resin and their mixtures. When present, the amount of viscosity enhancer in the overcoat is between about 2% by weight and about 20% by weight based on the total weight of the overcoat. When the solid dosage form is overcoated as described herein, the rate of drug release is no longer in the order of zero when the same drug that is inside the matrix core is used in the overcoat. When a drug other than that used in the overcoat is used in the matrix core, the release rate of the drug that is inside the matrix core is in the order of zero, but the drug release rate of the drug that is in the overcoat is not in the order of zero. In some cases, the overcoat contains between about 25% by weight and about 77% by weight of pharmaceutical agent, between about 23% by weight and about 75% by weight of soluble polymer in water, up to about 50% by weight non-stick, up to about 10% by weight of stabilizer and up to about 20% by weight of viscosity enhancer. In other cases, the overcoat includes between about 36% by weight and about 45% by weight of the pharmaceutical agent, between about 55% and about 64% by weight of the water-soluble polymer, up to about 5% by weight of the antiadherent, up to about 1% by weight of the stabilizer and up to about 2% by weight of the viscosity enhancer. In some embodiments, the weight ratio between the water soluble polymer and the pharmaceutical agent in the overcoat is between about 0.3: 1 and about 3.0: 1, preferably between about 1.2: 1 and about 1.8: 1. The matrix core, the overcoat, the modified release coating and / or the barrier coating may include other conventional excipients known in the art. By selecting and combining excipients, solid dosage forms can be provided that exhibit improved performance with respect to, among other properties, efficacy, bioavailability, purification time, stability, safety, dissolution profile, disintegration and / or other pharmacokinetic, chemical and / or physical properties.

When the composition is formulated as a tablet, the combination of the selected excipients provides tablets which may exhibit an improvement in, among other properties, the dissolution profile, the hardness, the compressive breaking strength and / or the friability. The solid dosage forms can be formulated in a variety of structures or physical forms, including tablets, lozenges, oblong tablets and the like. A specialized geometry of the matrix core in the present invention is not necessary. The matrix core may have any form known in the pharmaceutical industry and suitable for the administration of drugs, such as spherical, cylindrical, or conical shape. The tablets are preferred. The methylphenidate formulations of the present invention can be administered to children and adults and their action preferably has a duration of about 6 hours and no more than about 10 hours. The methylphenidate formulation of the invention should be taken at breakfast and is designed to eliminate the need for administration at school or work during lunch. If a patient requires more than 10 hours of treatment per day, he should take another dose of immediate-release methylphenidate at dinner. If the patient requires 24-hour treatment, he must take another dose of the formulation of the invention at dinner. The solid dosage forms of the present invention are made by a simple method under ambient conditions without the use of expensive manufacturing equipment. Other methods, such as wet granulation, are more expensive, slower, include more excipients and require more capital goods. The method provides ease of manufacture and drug release substantially linearly over a prolonged period. The method comprises mixing the hydrophobic material, between about 4 and 14% by weight of the water-soluble pharmaceutical agent, the optional filler, the optional release modifier, the optional lubricant and the optional glide to form a mixture and the compression of 1st mix In one embodiment, the mixture comprises no more than about 9, 10, 11, 12 or 13% by weight of water soluble pharmaceutical agent. The mixture can be prepared and / or compressed under ambient conditions. Any conventional direct compression method is suitable for preparing the matrix core. If the dosage form is to include a barrier coating, the matrix core is coated with a water soluble polymer, optionally mixed with an anti-adherent, to form a barrier coating surrounding the matrix core. Coating methods they are well known in the art. Once the barrier coating is dry, it is coated with the modified release coating. Once the modified release coating is dried, the dosage form can be stored. The solid dosage form is capable of releasing the pharmaceutical agent at a rate in the order of zero over a period of at least 4, 5, 6, 7, 8, 9 or 10 hours after administration to a subject. If a barrier coating is not included, the modified release coating is applied to the matrix core and dried to form the solid dosage form. If the dosage form is to include an overcoat, the matrix core, coated with modified release coating, is coated with a mixture of the water soluble pharmaceutical agent, the water soluble polymer, the optional non-stick, the optional stabilizer and the optional viscosity enhancer, and it dries. Conventional coating methods can be used. The dosage form on coated can be stored. In one embodiment, the active pharmaceutical agent is placed in a V-blender or the like with the hydrophobic material, the optional filler, the optional release modifier, the optional lubricant and the optional glide and mixed for several minutes under environmental The mixture is compressed using a Korsch PH 106 compressor or other common compression equipment at ambient conditions without using heat or solvent to form the matrix core. The matrix core is then coated with the optional barrier coating and / or the modified release coating using a Vector Hi-coater coating equipment or other equivalent. For example, methylphenidate hydrochloride is placed in a V-mixer with ethylcellulose and microcrystalline cellulose with silica and mixed for five minutes. Subsequently, colloidal silicon dioxide is added as a glidant and the mixture is mixed for another five minutes. The mixture is compressed in a Korsch PH 106 compressor at ambient conditions. The resulting matrix core is then coated with an optional hypromellose coating and / or a modified release coating containing optional hypromellose, ethylcellulose and triacetin, using Vector Hi-coater coating application equipment. EXAMPLES The following non-limiting examples are set forth to further illustrate the present invention. Experienced technicians should perceive that the techniques described in the following examples represent the approaches that the inventors found to work well in the practice of the invention and can therefore be considered to be they are examples of ways to practice it. However, experienced technicians should, in light of the present disclosure, perceive that many changes can be made in the specific embodiments disclosed and still obtain a similar or similar result without departing from the spirit and scope of the invention. Example 1 Methylphenidate hydrochloride was placed in a V-blender with ethylcellulose, hydroxypropylcellulose and microcrystalline cellulose with silica and mixed for five minutes. Subsequently, magnesium stearate was added as a lubricant and the mixture was mixed for another five minutes. Then, the mixture was compressed using a Korsch compressor PH 106 at ambient conditions to form a matrix core. The matrix core contained the ingredients in the following table.

Methylphenidate hydrochloride was the pharmaceutical agent soluble in water, ethylcellulose was the material hydrophobic, the high viscosity hydroxypropylcellulose was the release modifier, the microcrystalline cellulose with silica was a filler and the magnesium stearate was used as a lubricant. In one embodiment, the tablets were not coated.

The release characteristics of the tablets were analyzed by placing the tablets in an aqueous solution of 0.1% formic acid (pH 2.6). The USP paddle apparatus at 50 rpm was used to mix the tablets in the acid solution. A total volume of 500 ml of the dissolution media was used. At 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours and 12 hours, the amount of methylphenidate hydrochloride dissolved in each test run was determined. The experimental results are illustrated in Figure 1A and determined by ultraviolet spectroscopy at 200 nm. Figure IB is a graphical representation of ln (100 -% dissolved methylphenidate hydrochloride) as a function of time and indicates a first-order drug release for uncoated matrix core tablets. In another embodiment, the matrix cores were coated with a modified release coating containing 70% SURELEASE ™ and 30% OPADRY ™ (solid content% w / w). The tablets were coated with varying amounts of coating, up to 8% by weight based on the weight increase of the tablet and some tablets were not they coated. The preferred amount of coating to achieve a release profile in the order of zero was determined experimentally by placing the tablets in 0.1% aqueous formic acid solution (pH 2.6). The USP paddle apparatus at 50 rpm was used to mix the tablets in the acid solution. A total volume of 500 ml of the dissolution media was used. At 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours and 12 hours, the amount of methylphenidate hydrochloride dissolved in each test run was determined. The experimental results are illustrated in Figure 2A and determined by ultraviolet spectroscopy at 200 nm. Figure 2B is a graphical representation of ln (100 -% dissolved methylphenidate hydrochloride) as a function of time and indicates drug release in the order of zero for coated tablets. Example 2 A matrix core was made according to the production method of Example 1. The matrix core contained the ingredients of the following table. Ingredient Weight (mg) Methylphenidate hydrochloride 21 Glyceryl behenate (COMPRITOL ™ 888 ATO) 31.25 Hydroxypropylcellulose (KLUCEL ™ EF) 12.25 Microcrystalline cellulose with silica (PROSOLV ™ HD90) 185.25 Colloidal silicon dioxide 5.0 Total 255 Methylphenidate hydrochloride was the water soluble pharmaceutical agent, low viscosity hydroxypropylcellulose was used as a release modifier, glyceryl behenate was added as a hydrophilic material and as a lubricant, microcrystalline cellulose with silica was a filler and dioxide of colloidal silicon was used as a glider. In one embodiment, the tablets were not coated.

The release characteristics of the tablets were analyzed by placing the tablets in the aqueous solution of 0.1% formic acid (pH 2.6). The USP paddle apparatus at 50 rpm was used to mix the tablets in the acid solution. A total volume of 500 ml of the dissolution media was used. At 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours and 12 hours, the amount of methylphenidate hydrochloride dissolved in each test run was determined. The experimental results are illustrated in Figure 3 and determined by ultraviolet spectroscopy at 200 nm. In another embodiment, the matrix cores were coated with a coating containing 70% SURELEASE ™ and 30% OPADRY ™ (solid content% w / w). The tablets were coated with varying amounts of coating, up to 8% by weight based on the weight increase of the tablet and some tablets were not coated. The preferred amount of coating to achieve a release profile in the order of zero was determined experimentally by placing the tablets in 0.1% aqueous formic acid solution (pH 2.6). The USP paddle apparatus at 50 rpm was used to mix the tablets in the acid solution. A total volume of 500 ml of the dissolution media was used. At 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours and 12 hours, the amount of methylphenidate hydrochloride dissolved in each test run was determined. The experimental results are illustrated in Figure 4A and determined by ultraviolet spectroscopy at 200 nm. Figure 4B is a graphical representation of ln (100 -% dissolved methylphenidate hydrochloride) as a function of time and indicates drug release in the order of zero for tablets with 6% and 8% coating. Example 3 After the matrix cores of Example 1 were formed, they were coated with a coating comprising 80% SURELEASE ™ and 20% OPADRY ™ (solid content% w / w). The tablets were coated with varying amounts of coating, up to 8% by weight based on the weight increase of the tablet and some tablets were not coated. The preferred amount of coating for achieving a release profile in the order of zero was determined experimentally by placing the tablets in an aqueous solution of 0.1% formic acid (pH 2.6). The USP paddle apparatus at 50 rpm was used to mix the tablets in the acid solution. A total volume of 500 ml of the dissolution media was used. At 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours and 12 hours, the amount of methylphenidate hydrochloride dissolved in each test run was determined. The experimental results are illustrated in Figure 5A and determined by ultraviolet spectroscopy at 200 nm. Figure 5B is a graphical representation of ln (100 -% dissolved methylphenidate hydrochloride) as a function of time indicating a release of the drug in the order of zero for tablets with 4% coating. It is assumed that tablets having a 6% or 8% polymer coating would have presented a release profile in the order of zero if the tests had extended beyond 12 hours. Example 4 After the matrix cores of Example 1 were formed, they were coated with a coating comprising 95% SURELEASE ™ and 5% OPADRY ™ (solid content% w / w). The tablets were coated with varying amounts of coating, up to 6% by weight based on the Weight gain of the tablet and some tablets were not coated. The preferred amount of coating to achieve a release profile in the order of zero was determined experimentally by placing the tablets in 0.1% aqueous formic acid solution (pH 2.6). The USP paddle apparatus at 50 rpm was used to mix the tablets in the acid solution. A total volume of 500 ml of the dissolution media was used. At 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours and 12 hours, the amount of methylphenidate hydrochloride dissolved in each test run was determined. The experimental results are illustrated in Figure 6 and were determined by ultraviolet spectroscopy at 200 nm. It is assumed that tablets having 5, or 6% polymeric coating would have presented a release profile in the order of zero if the tests had extended beyond 12 hours. Example 5 The matrix core tablets were prepared as in Example 1. These were coated with a mixture of ethylcellulose and hypromellose in a 70:30 w / w ratio. The tablets were placed in an oven at a temperature of 50 ° C for up to 7 days. The dissolution profiles of the tablets were compared before and after heating in an oven. The uncoated matrix tablets provided a dissolution profile with first-order kinetics. When these matrix tablets were coated to a total weight increase of at least 6% by weight, a slower dissolution rate of the drug with characteristics in the order of zero was observed. However, when the coated tablets were placed in an oven at 50 ° C, the dissolution rate increased and the shape of the profile reverted to first order kinetics. This was attributable to the observed breakage of the polymeric coating near the edges of the central band of the tablets. As a result of the failure of the coating, the shape of the drug release profile of the coated tablets acquired that of the core matrices. The rupture of the polymer film can be the result of one or more of the following: (i) brittleness of the hybrid polymer film; (ii) expansion of the tablet core during heating in the oven and / or dissolution in vitro; and (iii) non-uniformity of the thickness of the polymer layer due to the preferential coating on the upper and lower faces of the surface of the tablet. This effect on the dissolution profile was eliminated by optimizing the level of plasticizer, which increased the flexibility of the film. The uniformity of the coating thickness was improved by the appropriate design of the tooling of the tablet. Other ways to prevent such cracking is to apply a barrier coating before application of the modified release coating. The same coating apparatus that was used in the previous examples was used to apply the barrier coating and then the modified release coating. The tablets were coated with 4% by weight of barrier coating, based on the weight increase of the matrix core and either 4% by weight or 6% by weight of the modified release coating, based on the weight increase of the tablet. , and some tablets were not coated. In Figure 8, tablets with 6% modified release coating were not cured (i.e., not heated to 50 ° C), or cured at 50 ° C for 1 day, or cured at 50 ° C during 7 days. The preferred amount of coating to achieve a release profile in the order of zero was determined experimentally by placing the tablets in 0.1% aqueous formic acid solution (pH 2.6). The USP paddle apparatus at 50 rpm was used to mix the tablets in the acid solution. A total volume of 500 ml of the dissolution media was used. At 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours and 12 hours, the amount of methylphenidate hydrochloride dissolved in each test run was determined. The experimental results are illustrated in Figures 7 and 8 and determined by ultraviolet spectroscopy at 200 nm. Visual observation revealed that the coating remained intact throughout the dissolution process. In another embodiment, tablets having a matrix core containing ethylcellulose and hypromellose in a ratio of 1: 3, a modified release coating and a barrier coating were prepared as described above, except that 6% coating Modified release included ethylcellulose, triacetin and hypromellose in a ratio of 70: 3.5: 26.5. The results are illustrated in Figure 9. The addition of a plasticizer to the modified release coating increased the flexibility of the coating on the cured tablets at 50 ° C. Example 6 A matrix core was made according to the production method of Example 1. The matrix core contained the ingredients of the following table.

(PROSOLV ™ HD90) Magnesium stearate 3 0 Total 300 300 The friability of the uncoated tablets was evaluated using a USP friability tester at 100 revolutions at different hardness values for both formulations. The results are shown in Figures 10 and 11, in which "kP" indicates kilo pounds), a unit of force to express the hardness or breaking force by compression of the pharmaceutical tablets and "kN" indicates to kilo Newtons, a compression force unit. The uncoated matrix core tablets prepared with various hardnesses and under various compression forces were also placed in 0.1% aqueous formic acid solution (pH 2.6). The USP paddle apparatus at 50 rpm was used to mix the tablets in the acid solution. A total volume of 500 ml of the dissolution media was used. At 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours and 12 hours, the amount of methylphenidate hydrochloride dissolved in each test run was determined. The experimental results are illustrated in Figures 12 and 13 and determined by ultraviolet spectroscopy at 200 nm. Example 7 The uncoated matrix cores were prepared as in Example 1 so as to contain the following ingredients. Upon dissolution, the matrix cores showed a dissolution similar to that reported for other matrix cores of the invention.

EXAMPLE 8 Matrix core tablets were prepared which included a barrier coating and were then coated with a modified release coating as described in the previous examples. These tablets were then overcoated with an overcoating solution and dried. The coated tablets were subsequently coated with a colored coating and dried to form the final tablet. The formulations were prepared to contain the ingredients indicated below: Weight of Ingredient Formula C Formula D (mg) (mg) Matrix core Methylphenidate hydrochloride 21 21 Hydroxypropylcellulose (KLUCEL ™ HXF) 25 25 Ethylcellulose (AQUALON ™ TIO EC) 75 75 Microcrystalline Cellulose with 126.5 126.5 Silica (PROSOLV ™ HD90) Magnesium Stearate 2.5 2.5 OPADRY ™ Barrier Coating TRANSPARENT 10.4 10.4 SURELEASE ™ TRANSPARENT Modified Release Coating 11.6 20.3 Triacetin 0.6 1.0 OPADRY ™ TRANSPARENT 4.4 7.7 Overcoating Methylphenidate hydrochloride 6 6 OPADRY ™ TRANSPARENT 9.8 10.5 OPADRY ™ II GRAY color coating 9.1 9.5 Total 301.9 315.4 Weight of Ingredient Formula E Formula F (mg) (mg) Matrix core Methylphenidate hydrochloride 42 42 The tablets of formulas E and F and the formula C were placed in aqueous 0.1% hydrochloric acid solution (pH 3.0). The USP paddle apparatus at 50 rpm was used to mix the tablets in the acid solution. A total volume of 500 ml of the dissolution media was used. At 30 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours and 12 hours, the amount of methylphenidate hydrochloride dissolved in each test run was determined. The Experimental results are illustrated in figures 14 and 15, respectively, and were determined by ultraviolet spectroscopy at 200 nm. When introducing elements of the present invention or their preferred embodiments, the articles "a", "the," "the" and "said (a)" are intended to indicate that there is one or more of the elements. The terms "comprising", "included (s) or included (s)", "having" and "containing" are intended to be inclusive and mean that there may be other elements than those mentioned elements. Considering the above, it will be seen that the various objects of the invention are achieved and other advantageous results are achieved. As there are several possible changes that could be made to the above methods without departing from the scope of the invention, it is intended that all the material contained in the description and that shown in any of the attached figures be construed as illustrative and not in any sense limiting It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims

CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. - A solid dosage form characterized in that it comprises: a matrix core comprising a hydrophobic material and a water-soluble pharmaceutical agent; and a modified release coating surrounding the matrix core, wherein the modified release coating comprises a hydrophobic polymer and a hydrophilic pore-forming agent; wherein the solid dosage form is capable of releasing the pharmaceutical agent at a rate of release in the order of zero over a period of at least four hours after administration to a subject.
2. - The dosage form according to claim 1 characterized in that it further comprises a barrier coating between the modified release coating and the matrix core so that the barrier coating surrounds the matrix core and the modified release coating surround the barrier coating.
3. The dosage form according to claim 1 or 2 characterized in that it is capable of releasing the pharmaceutical agent at a rate of release in the order of zero over a period of at least 5, 6, 7, 8, 9 or 10 hours after administration to a subject.
4. - The dosage form according to any of the preceding claims characterized in that the solid dosage form is able to release the pharmaceutical agent at a rate of release in the order of zero in the span between about six and about ten hours after of administration to a subject.
5. - The dosage form according to any of the preceding claims characterized in that the water soluble pharmaceutical agent comprises abacavir sulfate, acyclovir, aminocaproic acid, alendronate sodium, amitriptyline hydrochloride, amphetamine, acetaminophen, allopurinol, amoxicillin, atenolol, atropine sulfate, azithromycin, balsalazide, benzepril hydrochloride, bisoprolol fumarate, bupropion hydrochloride, buformin, calaciclovir, captopril, cefprozil, cetrizine hydrochloride, cimetidine, ciprofloxacin, clindamycin, chlorpheniramine maleate, chlorpromazine hydrochloride, clomipramine hydrochloride, clonidine hydrochloride, clopidogrel bisulfate, cloxacillin sodium, codeine phosphate, colchicines, cyclophosphamide, diethylcarbamazine citrate, diltiazem, doxycycline, doxepin, DL-methionine, eprosartan, Etembutol hydrochloride, ethosuximide, erythromycin, fexofenadine, ferrous sulfate, fluoxetine hydrochloride, fluvastatin, fosinopril sodium, gabapentin, hydralazine hydrochloride, hydrocodone bitartrate, hydroxyzine hydrochloride, hydroxyurea, indinavir sulfate, isoniazid, isosorbide mononitrate, lactobionate, lamivudine, levamisole hydrochloride, levofloxacin, lisinopril, losartan potassium, metformin hydrochloride, methylphenidate, methylphenidate hydrochloride, metoprolol tartrate, minocycline hydrochloride, montelukast sodium, naproxen sodium, neostigmine bromide, nicotinamide, niacin, nifurtimox, nortriptyline hydrochloride , olanzepine, oxybutynin chloride, penicillamine, penicillin V potassium, phenytoin sodium, phenformin, pramipexole, pravastatin sodium, potassium chloride, primaquine phosphate, promethazine, promethazine hydrochloride, propanolol hydrochloride, propoxyphene hydrochloride, pseudoephedrine hydrochloride, bromide of piridostigmi na, pyridoxine hydrochloride, quinapril hydrochloride, quetiapine, ramipril, ranitidine hydrochloride, reboxetine, risedronate sodium, rosiglitazone maleate, sildenafil, sodium valproate, salbutamol sulfate, stavudine, sumanirol, sumatriptan succinate, terazosin hydrochloride, hydrochloride tetracycline, timolol maleate, tramadol hydrochloride, valaciclovir hydrochloride, vancomycin, hydrochloride venlafaxine, verapamil hydrochloride, warfarin sodium or combinations thereof.
6. - The dosage form according to claim 5 characterized in that the water-soluble pharmaceutical agent is methylphenidate hydrochloride.
7. - The dosage form according to any of the preceding claims characterized in that the hydrophobic material comprises a glyceride, hydrogenated castor oil, a hydrogenated vegetable oil, a water-insoluble cellulose, a wax, a substance similar to wax, a fat, an oil, a fatty acid, an emulsifier, a modified starch, a fatty alcohol, a protein, lacquer or a polymer.
8. - The dosage form according to claim 7 characterized in that the glyceride comprises glyceryl behenate, glyceryl trimyristate, glyceryl trilaurate, glyceryl tristearate, glyceryl monostearate, glyceryl palmito stearate or glyceryl triacetate.
9. The dosage form according to claim 7, characterized in that the wax comprises carnauba wax, cetyl esters wax, beeswax, castor wax, cationic emulsifying wax, cetrimide emulsifying wax, an emulsifying wax, microcrystalline wax , a non-ionic wax, a non-ionic emulsifying wax, paraffin, petroleum wax, ceresin oil wax, whale sperm wax, white wax or yellow wax.
10. The dosage form according to claim 7, characterized in that the water-insoluble cellulose comprises ethylcellulose, cellulose acetate, cellulose acylate, cellulose diacylate, cellulose triacilate, cellulose acetate butyrate, cellulose acetate propionate, nitrocellulose , cellulose diacetate or cellulose triacetate.
11. The dosage form according to claim 7, characterized in that the hydrophobic material comprises a polymer selected from the group consisting of a polyolefin, a polyurethane, a polyvinyl chloride, a polyvinyl acetate, a polymer of acrylic acid, a methacrylic acid polymer and its mixtures.
12. The dosage form according to any of the preceding claims characterized in that the hydrophobic polymer comprises ethylcellulose, cellulose acetate, cellulose acylate, cellulose diacylate, cellulose triacilate, cellulose acetate butyrate, cellulose acetate propionate, nitrocellulose , cellulose diacetate, cellulose triacetate, a copolymer of methacrylate, polyvinyl chloride, polyvinyl acetate, polymethyl methacrylate, polyethylacrylate, polyvinyl chloride, polyethylene, polypropylene, polyisobutylene, polyethyl methacrylate trimethylammonium or a block polymer or copolymer thereof.
13. The dosage form according to claim 12, characterized in that the hydrophobic polymer comprises ethylcellulose.
14. The dosage form according to any of the preceding claims characterized in that the hydrophilic pore-forming agent comprises a polymer, a cellulose, a cellulose ether, a protein, a protein derivative, a saccharide, a polysaccharide or a salt of an alkali metal.
15. The dosage form according to claim 14, characterized in that the hydrophilic pore-forming agent comprises a cellulose selected from the group consisting of hypromellose, hypromellose phthalate, methylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethyl hydroxyethylcellulose, ethylhydroxyethylcellulose , ethyl methyl cellulose, hydroxyethyl methyl cellulose, hydroxymethyl cellulose and hydroxymethyl propyl cellulose.
16. The dosage form according to claim 15, characterized in that the hydrophilic pore-forming agent comprises hypromellose.
17. The dosage form according to claim 15, characterized in that the hydrophilic pore-forming agent comprises a polymer selected from the group which consists of polyvinylpyrrolidone, a polyalkylene oxide and a polyalkylene glycol.
18. - The dosage form according to claim 15 characterized in that the hydrophilic pore forming agent comprises a polysaccharide selected from the group consisting of polydextrose, guar gum, hydroxypropyl guar, alginate, xanthan gum and carboxymethyl hydroxypropyl guar.
19. - The dosage form according to claim 15 characterized in that the hydrophilic pore-forming agent comprises a saccharide selected from the group consisting of pullulan, dextrin, sucrose, glucose, fructose, mannitol, lactose, mannose, galactose and sorbitol.
20. The dosage form according to claim 15, characterized in that the hydrophilic pore-forming agent comprises a salt of an alkali metal selected from the group consisting of lithium carbonate, sodium chloride, sodium bromide, potassium chloride, potassium sulfate, potassium phosphate, sodium acetate and sodium citrate.
21. - The dosage form according to any of the preceding claims characterized in that the matrix core comprises between about 10 and about 50% by weight of hydrophobic material, between about 2 and about 25% by weight of agent water-soluble pharmaceutical, up to about 5% by weight of lubricant, up to about 75% by weight of filler, up to about 25% by weight of release modifier and up to about 10% by weight of glidant.
22. The dosage form according to claim 20, characterized in that the matrix core comprises between approximately 12 and approximately 40% by weight of hydrophobic material, between approximately 4 and approximately 16% by weight of water-soluble pharmaceutical agent, among about 0.5% by weight and about 3% by weight of lubricant, between about 50 and about 70% by weight of filler, between about 5 and about 20% by weight of release modifier, and between about 2 and about 7% by weight slider weight.
23. - The dosage form according to claim 21, characterized in that the matrix core comprises between approximately 19 and approximately 30% by weight of hydrophobic material, between approximately 5 and approximately 11% by weight of water-soluble pharmaceutical agent, among about 1 and about 2% by weight of lubricant, between about 50 and about 58% by weight of filler, between about 10 and about 17% by weight of release modifier, and between about 2 and about 4% by weight of glidant.
24. - The dosage form according to any of the preceding claims characterized in that the matrix core includes a filling composed of microcrystalline cellulose, sodium citrate, dicalcium phosphate, colloidal silicon dioxide, starches, lactose, sucrose, glucose, mannitol and silicic acid, alginates, gelatin, polyvinylpyrrolidinone, lactitol, dextrose, acacia, hypromellose, hydroxypropylcellulose, hydroxyethylcellulose, starch or pregelatinized starch.
25. - The dosage form according to claim 24 characterized in that the filler comprises microcrystalline cellulose.
26. - The dosage form according to any of the preceding claims characterized in that the matrix core includes a release modifier composed of a hydrophilic cellulose, a saccharide, a polysaccharide, polyvinylpyrrolidone or zein.
27. - The dosage form according to claim 26 characterized in that the release modifier comprises hydrophilic cellulose selected from the group consisting of hydroxypropylcellulose, hypromellose, hypromellose phthalate, methylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, carboxymethyl hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, ethyl methyl cellulose, hydroxyethyl methyl cellulose or hydroxymethyl propyl cellulose.
28. - The dosage form according to claim 26 characterized in that the release modifier comprises the saccharide selected from the group consisting of pullulan, dextrin, sucrose, glucose, fructose, mannitol, lactose, mannose, galactose and sorbitol.
29. - The dosage form according to claim 26 characterized in that the release modifier comprises the polysaccharide selected from the group consisting of polydextrose, guar gum, hydroxypropyl guar, alginate, polysorbate, xanthan gum and carboxymethyl hydroxypropyl guar.
30. - The dosage form according to any of the preceding claims characterized in that the matrix core includes a lubricant composed of a glyceride, a metal stearate, talc, stearic acid, sodium benzoate, sodium chloride, leucine, polyethylene glycol, magnesium lauryl sulfate, a hydrogenated vegetable oil, colloidal silica, a wax, boric acid, sodium acetate, sodium fumarate, DL-leucine, sodium oleate or sodium lauryl sulfate.
31. The dosage form according to claim 30, characterized in that the lubricant comprises the glyceride selected from the group consisting of glyceryl behenate, glyceryl trimyristate, trilaurate. of glyceryl, glyceryl tristearate, glyceryl monostearate, glyceryl palmitostearate and glyceryl triacetate.
32. The dosage form according to claim 30, characterized in that the lubricant comprises the metal stearate selected from the group consisting of magnesium stearate, zinc stearate, calcium stearate, sodium stearate and aluminum stearate.
33.- The dosage form according to any of the preceding claims characterized in that the matrix core includes a slide composed of colloidal silicon dioxide, aluminum silicate, talc, powdered cellulose, magnesium trisilicate, silicon dioxide, kaolin , glycerol monostearate, a metal stearate, titanium dioxide or starch.
34. - The dosage form according to any of the preceding claims characterized in that the modified release coating further comprises a plasticizer.
35. The dosage form according to claim 34, characterized in that the plasticizer comprises triacetin, methyl abietate, acetyl tributyl citrate, acetyl triethyl citrate, diisooctyl adipate, amyl oleate, butyl ricinoleate, benzoate. of benzyl, butyl and glycol esters of fatty acids, butyl carbonate and diglycol, butyl oleate, butyl stearate, di (β-methoxyethyl) adipate, dibutyl sebacate, dibutyl tartrate, diisobutyl adipate, dihexyl adipate , di (2-ethylbutyrate) of triethylene glycol, di (2-ethylhexoate) of polyethylene glycol, diethylene glycol monolaurate, monomeric polyethylene ester, hydrogenated rosin methyl ester, methoxyethyl oleate, butoxyethyl stearate, butyl phthalyl butyl glycolate, glycerol tributyrate , triethylene glycol dipelargonate, β- (p-ter-amylphenoxy) ethanol, β- (p-tert-butylphenoxy) ethanol, β- (p-tert-butylphenoxyethyl) acetate, bis ^ -p-tert-butylphenoxydiethyl ether), camphor, a petroleum based hydrocarbon, diamyl phthalate, (diamylphenoxy) ethanol, diphenyl oxide, hydrobicylalcohol, becholine, acetyl tributyl citrate, polyethylene glycol, castor bean oil or glyceryl triacetate.
36. - The dosage form according to claim 35, characterized in that the plasticizer comprises triacetin.
37. - The dosage form according to any of the preceding claims characterized in that the modified release coating further comprises an anti-adherent.
38.- The dosage form in accordance with Any of the preceding claims characterized in that the modified release coating comprises between about 5 and about 70% by weight of hydrophobic polymer, between about 30 and about 95% by weight of hydrophilic pore-forming agent, up to about 40% by weight of plasticizer and up to 50% by weight of anti-adherent.
39. - The dosage form according to any of the preceding claims characterized in that the modified release coating comprises between about 20 and about 60% by weight of hydrophobic polymer, between about 40 and about 80% by weight of pore forming agent hydrophilic, between about 20 and about 35% by weight of plasticizer, and up to 20% by weight of anti-adherent.
40. The dosage form according to any of the preceding claims characterized in that the modified release coating comprises between about 25 and about 55% by weight of hydrophobic polymer, between about 45 and about 75% by weight of pore forming agent hydrophilic, between about 20 and about 30% by weight of plasticizer, and up to 10% by weight of anti-adherent.
41. - The dosage form according to any of claims 1 to 38 characterized in that the modified release coating comprises at least 20% by weight of plasticizer.
42. The dosage form according to any of the preceding claims, characterized in that the weight ratio between hydrophobic polymer and hydrophilic pore-forming agent is between about 1: 1 and about 9: 1.
43. - The dosage form according to claim 42, characterized in that the weight ratio between hydrophobic polymer and hydrophilic pore-forming agent is between about 1: 1 and about 4: 1.
44. - The dosage form according to claim 43 characterized in that the weight ratio between hydrophobic polymer and hydrophilic pore-forming agent is between about 1.25: 1 and about 2.33: 1.
45. - The dosage form according to any of claims 2 to 44 characterized in that the barrier coating comprises a water soluble polymer.
46.- The dosage form according to claim 45 characterized in that the water soluble polymer comprises hypromellose, hypromellose phthalate, methylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethyl hydroxyethyl cellulose, ethyl hydroxyethyl cellulose, ethyl methyl cellulose, hydroxyethyl methyl cellulose, hydroxymethyl cellulose, hydroxymethyl propyl cellulose, polyvinyl alcohol, polyvinyl pyrrolidone, a polyalkylene oxide, a polyalkylene glycol, a polymer of acrylic acid, a copolymer of vinyl acetate, a polysaccharide, a copolymer of methacrylic acid or a copolymer of maleic anhydride / methyl vinyl ether.
47. The dosage form according to claim 45, characterized in that the barrier coating comprises hypromellose.
48. - The dosage form according to any of claims 45 to 47 characterized in that the barrier coating further comprises an anti-adherent.
49.- The dosage form according to any of claims 2 to 48, characterized in that the barrier coating represents an increase in weight between approximately 2 and approximately 6% by weight based on the total weight of the matrix core.
50.- The dosage form according to claim 49, characterized in that the barrier coating represents an increase in weight between approximately 3 and approximately 5% by weight based on the total weight of the matrix core.
51.- The dosage form in accordance with the claim 50 characterized in that the barrier coating represents an increase in weight between about 3.5 and about 4.5% by weight based on the total weight of the matrix core.
52. The dosage form according to any of the preceding claims characterized in that it further comprises an overcoat surrounding the modified release coating, wherein the overcoat comprises a pharmaceutical agent and a water soluble polymer.
53. - The dosage form according to claim 52 characterized in that the pharmaceutical agent is a water soluble pharmaceutical agent.
54. The dosage form according to claim 53, characterized in that the water-soluble pharmaceutical agent of the overcoat is the same as that of the matrix core.
55. The dosage form according to any of claims 52 to 54, characterized in that the water-soluble polymer comprises hypromellose, hypromellose phthalate, methylcellulose, sodium carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, carboxymethyl hydroxyethyl cellulose, ethylhydroxyethylcellulose, ethylmethyl. cellulose, hydroxyethyl methyl cellulose, hydroxymethyl cellulose, hydroxymethyl propyl cellulose, alcohol polyvinyl, polyvinylpyrrolidone, a polyalkylene oxide, a polyalkylene glycol, an acrylic acid polymer, a copolymer of vinyl acetate, a polysaccharide, a copolymer of methacrylic acid or a copolymer of maleic anhydride / methyl vinyl ether.
56. - The dosage form according to claim 55, characterized in that the overcoat comprises hypromellose.
57. - The dosage form according to any of claims 52 to 56, characterized in that the overcoating also comprises an anti-adherent.
58. - The dosage form according to claim 57, characterized in that the anti-adherent comprises talc, glyceryl monostearate, magnesium stearate, calcium stearate, stearic acid or mixtures thereof.
59. - The dosage form according to any of claims 52 to 58 characterized in that the overcoating further comprises a viscosity enhancer.
60. - The dosage form according to claim 59, characterized in that the viscosity enhancer comprises a sugar, a cellulose derivative, a polysaccharide, a pectin, agar, carrageenan, a hydrophilic gum, alginic acid, an alginate, dextrin, a resin carbomer or its mixtures.
61. - The dosage form according to any of claims 52 to 60 characterized in that the overcoat further comprises a stabilizer.
62. - The dosage form according to any of claims 52 to 61, characterized in that the overcoat also comprises a plasticizer.
63.- The dosage form according to claim 62, characterized in that the plasticizer comprises triacetin, methyl abietate, acetyl tributyl citrate, acetyl triethyl citrate, diisooctyl adipate, amyl oleate, butyl ricinoleate, benzyl benzoate, esters of butyl and glycol of fatty acids, butyl carbonate and diglycol, butyl oleate, butyl stearate, di (β-methoxyethyl) adipate, dibutyl sebacate, dibutyl tartrate, diisobutyl adipate, dihexyl adipate, di ( 2-ethylbutyrate) of triethylene glycol, di (2-ethylhexoate) of polyethylene glycol, diethylene glycol monolaurate, monomeric polyethylene ester, hydrogenated rosin methyl ester, methoxyethyl oleate, butoxyethyl stearate, butyl phthalyl butyl glycolate, glycerol tributyrate, dipelargonate triethylene glycol, ß- (p-ter-amylphenoxy) ethanol, ß- (p-tert-butylphenoxy) ethanol, ß- (p-tert-butylphenoxyethyl) acetate, bis (| 3-p-tert-butylphenoxydiethyl) ether, camphor, a petroleum-based hydrocarbon, diamyl phthalate, (diamylphenoxy) ethanol, diphenyl oxide, hydrobicylalcohol, becoline , acetyl tributyl citrate, polyethylene glycol, blown castor oil or glyceryl triacetate.
64. - The dosage form according to any of claims 52 to 63 characterized in that the overcoat represents an increase in weight between about 2 and about 25% by weight based on the total weight of the solid dosage form.
65. - The dosage form according to any of claims 52 to 64 characterized in that the overcoat comprises between about 25% by weight and about 77% by weight of pharmaceutical agent, between about 23% by weight and about 75% by weight. weight of water-soluble polymer, up to about 50% by weight of anti-adherent, up to about 10% by weight of stabilizer and up to about 20% by weight of viscosity enhancer.
66. - The dosage form according to any of claims 52 to 65, characterized in that the overcoat comprises between about 36% by weight and about 45% by weight of pharmaceutical agent, between about 55% by weight and about 64% by weight of water-soluble polymer, up to about 5% by weight of anti-adherent, up to about 1% by weight of stabilizer and up to about 2% by weight of viscosity enhancer.
67. - The dosage form according to any of claims 52 to 66 characterized in that the weight ratio between the water soluble polymer and the pharmaceutical agent is between about 0.3: 1 and about 3.0: 1.
68.- The dosage form according to claim 67, characterized in that the weight ratio between the water soluble polymer and the pharmaceutical agent is between about 1.2: 1 and about 1.8: 1 69. - The dosage form in accordance with any of the preceding claims characterized in that it is in the form of a tablet. 70. - A method of manufacturing a solid dosage form characterized in that it comprises: mixing a hydrophobic material, between about 2 and 14% by weight of a water-soluble pharmaceutical agent, an optional filler, an optional lubricant and an optional slider for form a mixture; and compress the mixture. 71. - The method according to claim 70 characterized in that the mixture comprises no more than about 9, 10, 11, 12 or 13% by weight of the water soluble pharmaceutical agent. 72. - The method according to claim 70 characterized in that the mixture comprises between about 4 and about 14% by weight of the water soluble pharmaceutical agent. 73. - The method according to claim 72 characterized in that the mixture comprises between about 5 and about 11% by weight of the water soluble pharmaceutical agent. 74. - The method according to any of claims 70 to 73 characterized in that the mixture is formed under ambient conditions. 75. - The method according to any of claims 70 to 74 characterized in that the mixture is compressed at ambient conditions. 76. - The method according to any of claims 70 to 75 characterized in that the mixture is compressed to form a matrix core, and the method further comprises the steps of coating the matrix core to form a barrier coating surrounding the matrix core, drying the barrier coating, coating the matrix core, coated with barrier coating, with a modified release coating and drying the release coating modified to form the solid dosage form, wherein the barrier coating comprises a water-soluble polymer, the modified release coating comprises a hydrophobic polymer and a hydrophilic pore-forming agent, and the solid dosage form is capable of releasing the agent pharmaceutical at a rate in the order of zero over a period of at least four hours after administration to a subject. 77. - The method according to any of claims 70 to 75 characterized in that the mixture is compressed to form a matrix core and the method further comprises the steps of coating the matrix core to form a modified release coating surrounding the core of matrix and drying of the modified release coating to form the solid dosage form, wherein the modified release coating comprises a hydrophobic polymer and a hydrophilic pore-forming agent, and the solid dosage form is capable of delivering the pharmaceutical agent to a speed in the order of zero over a period of at least four hours after administration to a subject. 78. - The method according to claim 76 or 77 characterized in that it also comprises the steps of coating the solid dosage form with an overcoating, wherein the envelope coating comprises a water soluble polymer and a pharmaceutical agent. 79.- A method for the preparation of a solid dosage form characterized in that it comprises: mixing a hydrophobic material, between approximately 2 and 25% by weight of a water-soluble pharmaceutical agent, an optional filler, an optional lubricant and an optional slider to form a mixture; compress the mixture to form a matrix core; coating the matrix core to form a barrier coating surrounding the matrix core; drying the barrier coating; coating the coated matrix core with barrier coating with a modified release coating; and drying the modified release coating to form the solid dosage form, wherein the barrier coating comprises a water soluble polymer, the modified release coating comprises a hydrophobic polymer and a hydrophilic pore forming agent, and the solid dosage form is able to release the pharmaceutical agent at a rate in the order of zero over a period of at least four hours after administration to a subject. 80. - A method for manufacturing a solid dosage form characterized in that it comprises: mixing a hydrophobic material, between about 2 and 25% by weight of a water-soluble pharmaceutical agent, an optional filler, an optional lubricant and an optional glide to form a me zc 1 a; compress the mixture to form a mat kernel; coating the matrix core to form a modified release coating surrounding the matrix core; and drying the modified release coating to form the solid dosage form, wherein the modified release coating comprises a hydrophobic polymer and a hydrophilic pore-forming agent, and the solid dosage form is capable of delivering the pharmaceutical agent at a rate of the order of zero for a period of at least four hours after administration to a subject. 81. The method according to claim 77 or 79 characterized in that the solid dosage form is manufactured according to any of claims 2 to
69. 82. The method according to any of claims 70 to 81, characterized in that the solid dosage form according to any of claims 1 to 69 is manufactured.